ABSTRACT/SUMMARY ? Project 4 Age-related hearing loss (ARHL)- presbycusis, is the leading neurodegenerative disorder, number 1 communication problem, and 1 of the top 3 chronic medical conditions (along with arthritis and cardiovascular disease) of our aged population. Project 4's primary thrust is to determine the age changes in sensory (cochlea) and neural (brain) circuitry involved when modulating of the progression of presbycusis, and discovery of age-linked changes in ARHL biomarkers. This new knowledge will pave the way for innovative behavioral, acoustic and drug interventions that prevent, slow down, or reverse this pervasive age-related medical condition. There are 3 Specific Aims that test an inter-related set of hypotheses: Specific Aim 1. Determine the degree to which hormonal supplementation prevents or slows down the progression of presbycusis. Experiments: Serum aldosterone alone and in combination with other anti-inflammatory agents will be given to aging rodents to prevent or slow the progression of ARHL. Neural and molecular metrics will be measured in aging animals undergoing hormone therapy, together with behavioral, physiological, and anatomical indices, including ear and brain-related hearing performance measures. Specific Aim 2. Determine the ability of enriched acoustic environments to arrest salient features of presbycusis. Experiments: Enriched acoustic environments will consist of extended, controlled exposure to specific artificially generated sounds presented within the animal holding environment (vivarium). Outcome measures will index hearing at ear and brain levels, at systems, cellular, and molecular levels. Specific Aim 3. Identify cellular and molecular pathway principles governing brain plasticity of central gain mechanisms in cases of ARHL. Experiments: Severity of central gain plasticity will be measured behaviorally (Project 2) and physiologically (Project 3) in aging mice. Relations between these quantitative metrics and biomarkers of central gain mechanisms will be examined, consistent with the goal of developing therapeutic interventions to optimize brain plasticity in the central auditory system. In sum, our innovative multidisciplinary team is on the cusp of significant translational advances to slow down or prevent key aspects of ARHL in older listeners. Carrying out the Specific Aims expeditiously should provide critical information for acoustic, technological and molecular/drug discovery innovative breakthroughs in our field. Note that in Specific Aim 1, we are close to identifying compounds for treating ARHL. Moreover, because of the interdisciplinary nature of our group, we could also uncover new findings in Specific Aims 2 and 3 that could point to a new drug or pharmacological agent, coupled with acoustical interventions or bio- therapies that would enhance their beneficial health effects.